The overall objective of this program is to develop a detailed understanding of the molecular and cellular mechanisms by which malaria parasites infect erythrocytes and induce anemia in their mammalian hosts. It is anticipated that the proposed study will lead to understanding how parasite proteins and their complexes interact with host receptors and signaling pathways to mediate (i) the establishment of infection in erythrocytes as well as (ii) clearance of uninfected erythrocytes in the peripheral circulation and ineffective erythropoiesis associated with malarial anemia. To achieve these goals three complementary projects that synergize at a superior level are proposed. 1) Determine whether signaling via erythrocyte raft associated Gs and parasite ligands that nucleate signaling raft complexes during parasite entry confer susceptibility to malarial infection and alter erythrocyte membrane properties. 2) Investigate parasite proteins and their complexes in erythrocyte adhesion and dyserythropoiesis in human malaria infections and murine models of malaria. 3) Establish non-human primate models of anemia to test mechanistic insights obtained from murine models, and develop and test insights for anemia associated with human malaria. To achieve these objectives a group of investigators with expertise in hematology, parasitology, cell biology, biochemistry, molecular biology, immunology, parasite genetics, functional genomics, rodent and non-human primate models have come together to mount a concerted effort. The information gathered in these studies is expected to lead to the development of therapeutic strategies against malarial infection and anemia.